Picropodophyllin is a compound belonging to the class of compounds denominated cyclolignans. The chemical structure of picropodophyllin is complex with a fused cyclic ring system and four adjacent chiral centra. The stereochemistry of the lactone ring exhibits a cis configuration by having two beta carbon-carbon bonds, i.e. the 8-9 and 8′-9′ bonds are located in or above the plane of the carbon ring. The hydroxy group and the trimethoxy benzyl ring are connected to the 7 and 7′ carbons, respectively, by alpha-bonds.

For a long time, picropodophyllin attracted little interest, since it was believed to possess no or low biological activity. In contrast, its stereoisomer podophyllotoxin, which has a trans configuration in the lactone ring, has been studied for decades due to its cytotoxic properties. Podophyllotoxin is also the starting material for the synthesis of Etoposide and other topoisomerase II inhibitors.

However, research has revealed that picropodophyllin does indeed exhibit interesting biological properties.
In WO 02/102804 it is disclosed that picropodophyllin is a specific and potent inhibitor of insulin-like growth factor-1 receptor (IGF-1R) and may be used in the treatment of IGF-1R dependent diseases such as various types of cancer, for instance malignant melanoma, Ewing's sarcoma, breast cancer, prostate cancer and leukemia, as well as in the treatment of psoriasis, arteriosclerosis and acromegaly. It is also mentioned that picropodophyllin may be used to potentiate the effects of anti-cancer drugs.
WO 2007/097707 discloses the use of picropodophyllin in the prophylaxis or treatment of diabetes mellitus type 2, nephropathy, retinopathy, macular degeneration, retinopathy of prematurity, central retinal vein occlusion, branch retinal vein occlusion, rubeotic glaucoma, thyroid eye disease, corneal graft rejection and corneal chemical burns; and for contraception.
WO 2009/157858 discloses the use of picropodophyllin for prophylaxis or treatment of diseases or conditions characterized by a hyperactive immune system such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, Alzheimer's disease, asthma, eczematous dermatitis, and graft rejection following transplantation.
Usually, picropodophyllin is obtained from its stereoisomer podophyllotoxin by epimerization. The major source of podophyllotoxin is several podophyllum species which mainly can be found in China. Because of the ease of extraction, Podophyllum emodi is a highly preferred plant, but this plant is difficult to cultivate and is becoming extinct in the wild which has caused the Chinese government to give this plant the highest level of protection. Podophyllum peltatum and Podophyllum versipelle constitute other plant sources of podophyllotoxin, but yield less pure podophyllotoxin upon extraction. Extraction of the podophyllum species yields podophyllotoxin, which has to be handled with great care because of its cytotoxic properties. The lack of easy access to the podophyllum species, the need for cautious handling of the poisonous plants and the cytotoxic podophyllotoxin, and the fact that podophyllum species are also used for extraction of other biologically active compounds are all factors that contribute to a high cost of goods and uncertain availability of podophyllotoxin as well as picropodophyllin.
A method converting podophyllotoxin into picropodophyllin is disclosed in Journal of Pharmaceutical Sciences, Vol. 75, No. 11, November 1986, Ole Buchardt et al., pages pp. 1076-1080. The yield of pure picropodophyllin is reported to be 78%.
The complex structures of podophyllotoxin and picropodophyllin have made them attractive targets for organic chemists interested in total synthesis of structurally complex compounds exhibiting biological activity, sometimes also with the aim of finding a synthetic route suitable to being performed on a large scale. Most of the published total synthesis aim at synthesizing podophyllotoxin, the drawbacks of which have been indicated above, which is subsequently epimerized into picropodophyllin at the end of the reaction sequence. For instance, synthetic routes involving epimerization of podophyllotoxin into picropodophyllin are described in Angew. Chem., Int. Ed., 2008, 47, p. 7557 and Org. Lett., 2009, 11(3), p. 597. It is a disadvantage to perform a crucial chemical reaction step at the end of a long reaction sequence since the value of the material, i.e. the compound undergoing transformations in the reaction sequence, increases with each reaction step and a failure at a late stage of the synthesis will therefore be expensive. Some publications mention synthetic routes wherein picropodophyllin is formed without going via podophyllotoxin. For instance, Angew. Chem., Int. Ed., 2008, 47, p. 7557 mentions such a route, but this route also produces a substantial amount of a by-product.
The synthetic route to podophyllotoxin (which can then be isomerized to picropodophyllin) used in Angew. Chem., Int. Ed., 2008, 47, p. 7557 is depicted in Scheme I.

Another publication mentioning a synthetic route for formation of picropodophyllin without going via podophyllotoxin is described in Chem. Commun., 2004, p. 184. However, when the inventors attempted to repeat this synthetic route problems were encountered during the synthesis of the enantiopure sulfoxide starting material. The difficulties of making the sulfoxide were confirmed by the authors of the Chem. Comm. article.
Thus, there remains a need for improved synthesis of picropodophyllin and derivatives thereof.
Abbreviations
    Cat. Catalytic    dba Dibenzylideneacetone    DCM Dichloromethane    DMSO Dimethyl Sulfoxide    equiv. Equivalents    EtOAc Ethyl acetate    g Gram    h Hour    HPLC High Performance Liquid Chromatography    LCMS Liquid Chromatography Mass spectrometry    M Molar    MS Mass Spectrosopy    mg Milligram    min Minute    mL Milliliter    mm Millimeter    mmol Millimol    NMO N-Methylmorpholine-N-Oxide    NMR Nuclear Magnetic Resonance    Pd(dppf)DCM: Pd(dppf)Cl2.CH2Cl2[1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II), complex with dichloromethane    Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0)    r.t. Room Temperature    Rt Retention time    Tf Triflyl, more formally known as trifluoromethanesulfonyl    OTf Triflate, more formally known as trifluoromethanesulfonate    TFA Trifluoro Acetic Acid    s singlet    d doublet    dd doublet of doublet    m multiplet    app apparent    wt-% Weight-%    vol-% Volume-%    Å Angstrom